CN110317132B - Preparation method of sodium phenylbutyrate - Google Patents
Preparation method of sodium phenylbutyrate Download PDFInfo
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- CN110317132B CN110317132B CN201910681637.4A CN201910681637A CN110317132B CN 110317132 B CN110317132 B CN 110317132B CN 201910681637 A CN201910681637 A CN 201910681637A CN 110317132 B CN110317132 B CN 110317132B
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- 229960002232 sodium phenylbutyrate Drugs 0.000 title claims abstract description 22
- VPZRWNZGLKXFOE-UHFFFAOYSA-M sodium phenylbutyrate Chemical compound [Na+].[O-]C(=O)CCCC1=CC=CC=C1 VPZRWNZGLKXFOE-UHFFFAOYSA-M 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 10
- 239000000463 material Substances 0.000 claims abstract description 10
- 239000000741 silica gel Substances 0.000 claims abstract description 10
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 8
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims abstract description 7
- PENAXHPKEVTBLF-UHFFFAOYSA-L palladium(2+);prop-1-ene;dichloride Chemical compound [Pd+]Cl.[Pd+]Cl.[CH2-]C=C.[CH2-]C=C PENAXHPKEVTBLF-UHFFFAOYSA-L 0.000 claims abstract description 7
- 239000012298 atmosphere Substances 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 6
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000000746 purification Methods 0.000 claims abstract description 5
- 238000010992 reflux Methods 0.000 claims abstract description 5
- ZGJLJEMLZMXNFD-UHFFFAOYSA-N but-3-enamide Chemical compound NC(=O)CC=[CH] ZGJLJEMLZMXNFD-UHFFFAOYSA-N 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- LHDWRNHALCCNAR-UHFFFAOYSA-N C1CCC(CC1)OP(=O)(C2=CC=CN2C3=CC=CC=C3)OC4CCCCC4 Chemical compound C1CCC(CC1)OP(=O)(C2=CC=CN2C3=CC=CC=C3)OC4CCCCC4 LHDWRNHALCCNAR-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000000539 dimer Substances 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 230000007812 deficiency Effects 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- JFLIEFSWGNOPJJ-JTQLQIEISA-N N(2)-phenylacetyl-L-glutamine Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CC1=CC=CC=C1 JFLIEFSWGNOPJJ-JTQLQIEISA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- PKJBWOWQJHHAHG-UHFFFAOYSA-N 1-bromo-4-phenylbenzene Chemical group C1=CC(Br)=CC=C1C1=CC=CC=C1 PKJBWOWQJHHAHG-UHFFFAOYSA-N 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种苯丁酸钠的制备方法。本发明通过在惰性气氛下，将材料和无水2,3‑丁二醇加入到反应容器中混匀；所述相关材料包括氯化烯丙基钯(II)二聚体、2‑(二环己基膦酰基)‑1‑苯基‑1H‑吡咯、N‑(八氨基喹啉)丁‑3‑烯酰胺、醋酸锂、溴苯、氰乙酸以及水；将反应容器置于125～135℃油浴中剧烈搅拌反应12小时，将反应产物经过硅胶柱纯化，得到带有导向基团的化合物；将化合物加入到含有氢氧化钠的乙醇溶剂中，并将混合物加热至130～140℃回流反应12小时，反应产物经减压蒸馏除去溶剂、萃取、收集水层、减压蒸馏除去水，得到苯丁酸钠制剂。本发明具有反应区域选择性及得率高、反应条件温和、反应及后处理纯化过程简单的特点。The invention discloses a preparation method of sodium phenylbutyrate. In the present invention, materials and anhydrous 2,3-butanediol are added into a reaction vessel and mixed under an inert atmosphere; the related materials include allylpalladium(II) chloride dimer, 2-(dimer) cyclohexylphosphono)-1-phenyl-1H-pyrrole, N-(octaaminoquinoline)but-3-enamide, lithium acetate, bromobenzene, cyanoacetic acid and water; place the reaction vessel at 125～135℃ The reaction was vigorously stirred in an oil bath for 12 hours, and the reaction product was purified by a silica gel column to obtain a compound with a guiding group; the compound was added to an ethanol solvent containing sodium hydroxide, and the mixture was heated to 130-140 ° C for reflux reaction After 12 hours, the solvent of the reaction product was distilled off under reduced pressure, extracted, the aqueous layer was collected, and the water was distilled off under reduced pressure to obtain a sodium phenylbutyrate preparation. The invention has the characteristics of high reaction zone selectivity and yield, mild reaction conditions, simple reaction and post-processing purification process.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of sodium phenylbutyrate.
Background
Sodium phenylbutyrate is a prodrug that is rapidly metabolized to phenylacetate. It can combine with glutamic acid and ammonia to produce phenylacetylglutamine, which is excreted by the kidney as yet another route for the excretion of nitrogenous wastes. Administration of sodium phenylbutyrate results in excessive blood ammonia and blood glutamate levels being reduced to form phenylacetylglutamine which increases the excretion of nitrogenous wastes. Is suitable for all the patients with enzyme deficiency of newborn (complete enzyme deficiency in 28 days after birth) and delayed enzyme deficiency with family history of high blood ammonia encephalopathy (partial enzyme deficiency after the first month of birth).
However, the existing synthetic method of sodium phenylbutyrate generally has the problems of more synthetic steps, poor reaction region selectivity, low product yield, mild reaction conditions, complex reaction and post-treatment purification processes and the like.
Disclosure of Invention
The invention aims to provide a preparation method of sodium phenylbutyrate, and aims to overcome the defects in the prior art.
The invention is realized in such a way that a preparation method of sodium phenylbutyrate comprises the following steps:
(1) under an inert atmosphere, mixing the material and anhydrous 2, 3-butanediol according to a molar volume ratio of 0.1 mmol: 1mL of the solution is added into a reaction container and mixed evenly; wherein the related materials comprise a molar ratio of 1: (1-3): (0.01-0.1): (0.02-0.2): (1-5): (1-3): (1-100) N- (octaaminoquinoline) but-3-enamide, bromobenzene, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid and water;
(2) placing the reaction container in an oil bath at 125-135 ℃ and violently stirring for reaction for 12 hours, and purifying a reaction product through a silica gel column to obtain a compound with a guide group;
(3) adding the compound into an ethanol solvent containing sodium hydroxide, and heating the mixture to 130-140 ℃ for reflux reaction for 12 hours; wherein the molar ratio of the compound to the sodium hydroxide to the ethanol is 1: (1.5-4): (5-50); and (3) distilling the reaction product under reduced pressure to remove the solvent, extracting, collecting a water layer, and distilling under reduced pressure to remove water to obtain the sodium phenylbutyrate preparation.
Preferably, in step (1), the inert gas used in the inert atmosphere is argon.
Preferably, in step (2), the silica gel column purification is a 1:20 petroleum ether to ethyl acetate wash chromatography silica gel column.
Preferably, in the step (3), the pressure of the reduced pressure distillation is within 100mbar, and the temperature is more than 80 ℃; the extraction was by addition of dichloromethane.
In order to overcome the defects and steps in the prior art, the invention discloses a preparation method of sodium phenylbutyrate. In the invention, the material and anhydrous 2, 3-butanediol are mixed in an inert atmosphere according to a molar volume ratio of 0.1 mmol: 1mL of the solution is added into a reaction container and mixed evenly; wherein the relevant materials include allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, N- (octaaminoquinoline) but-3-enamide, lithium acetate, 4-bromobiphenyl, cyanoacetic acid, and water; and (3) placing the reaction container in an oil bath at 125-135 ℃ to violently stir for reaction for 12 hours, and purifying the reaction product by a silica gel column to obtain the compound 4-phenyl-N- (quinoline-8-yl) butyramide with the guide group.
The compound can be used for synthesizing sodium phenylbutyrate, and the synthesis reaction process of the sodium phenylbutyrate is as follows:
compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects: according to the invention, through reduction HECK reaction, the octaaminoquinoline is designed as a compound of a guide group to control the region and chemical selectivity in the reaction, so that the problem of excessive steps in the existing sodium phenylbutyrate synthesis process is effectively solved; in addition, the method has the characteristics of high reaction area selectivity and yield, mild reaction conditions and simple reaction and post-treatment purification processes.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
(1) Under an argon atmosphere, mixing the material and anhydrous 2, 3-butanediol according to a molar volume ratio of 0.1 mmol: 0.1mL of the solution is added into a reaction vessel and mixed evenly; wherein the related materials comprise a molar ratio of 1: 3: 0.01: 0.2: 5: 3: 100 of N- (octaaminoquinoline) but-3-enamide, bromobenzene, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid and water;
(2) placing the reaction vessel in an oil bath at 125 ℃ and vigorously stirring for reacting for 12 hours, purifying the reaction product by a silica gel column (washing the silica gel column by using petroleum ether and ethyl acetate in a ratio of 1: 20) to obtain a compound with a guide group, and determining that the compound is 4-phenyl-N- (quinoline-8-yl) butyramide by detection.
Example 2
This embodiment is substantially the same as embodiment 1, with the difference that:
in step (1), the molar ratio of N- (octaaminoquinoline) but-3-enamide, bromobenzene, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid and water is 1: 1: 0.1: 0.02: 1: 1: 1;
in step (2), the oil bath temperature was 130 ℃.
Example 3
This embodiment is substantially the same as embodiment 1, with the difference that:
in step (1), the molar ratio of N- (octaaminoquinoline) but-3-enamide, bromobenzene, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid and water is 1: 2: 0.05: 0.1: 3: 2: 50;
in step (2), the oil bath temperature was 135 ℃.
Example 4
(1) Adding the 4-phenyl-N- (quinoline-8-yl) butanamide prepared in the example 2 into an ethanol solvent containing sodium hydroxide, and heating the mixture to 130-140 ℃ for reflux reaction for 12 hours; wherein the mol ratio of the 4-phenyl-N- (quinoline-8-yl) butyramide to the sodium hydroxide to the ethanol is 1: 4: 50;
(2) and (2) removing the solvent from the reflux reaction product in the step (1) by reduced pressure distillation (the pressure is within 100mbar and the temperature is more than 80 ℃), adding dichloromethane for extraction for 3 times, collecting a water layer, and removing the reaction solvent (mainly water) in the reaction product by a reduced pressure distillation method (the pressure is within 100mbar and the temperature is more than 80 ℃), thus obtaining the sodium phenylbutyrate preparation 1.
Example 5
This example is essentially the same as example 1, yielding sodium phenylbutyrate formulation 2, with the following differences: in the step (1), the molar ratio of the 4-phenyl-N- (quinoline-8-yl) butanamide to the sodium hydroxide to the ethanol is 1: 1.5: 5.
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (4)
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| CN115215798B (en) * | 2022-06-10 | 2024-02-06 | 恒升德康(南京)医药科技有限公司 | Aromatic cyanation synthesis method of inert olefin |
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| CN1511133A (en) * | 2001-05-21 | 2004-07-07 | R������˹�� ˹̹��˹�� | Synthesis of 4-phenylbutyric acid |
| CN1791606A (en) * | 2003-05-16 | 2006-06-21 | 德古萨股份公司 | Nitrogen-containing monodentate phosphines and their use in catalysis |
| CN108658857A (en) * | 2018-06-14 | 2018-10-16 | 南京工业大学 | Method for synthesizing carboxylic acid derivative |
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| CN1511133A (en) * | 2001-05-21 | 2004-07-07 | R������˹�� ˹̹��˹�� | Synthesis of 4-phenylbutyric acid |
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| CN108658857A (en) * | 2018-06-14 | 2018-10-16 | 南京工业大学 | Method for synthesizing carboxylic acid derivative |
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